A great variety of naphthols are known and useful as dyes and color indicators. Among these are naphthalene sulfonic acid compounds such as calcomine orange, which has been taught useful as an inert background dye in assaying peroxidatively active substances by U.S. Pat. No. 5,089,420, issued Feb. 18, 1992, inventors Albarella et al. Calcomine orange has been reported (Available Chemicals Database) to have the asymmetrical structure shown by Compound A: ##STR1##
U.S. Pat. No. 5,589,510, issued Dec. 31, 1996, inventors Ono et al., disclose a method for inhibiting retroviral infection by administering a naphthalenesulfonic acid compound represented by the Compound B: ##STR2## wherein R.sup.11 to R.sup.27 are individually selected from the group consisting of hydrogen atom, hydroxyl group, amino group which is optionally substituted with alkyl or aryl groups, sulfo groups, carboxyl groups, amide group which is optionally substituted with alkyl or aryl groups, acylamino groups, sulfonamide groups, sulfonylamino groups, alkoxy groups and halogen atoms; provided that at least one of R.sup.11 to R.sup.17 is hydroxyl or amino group, at least one of R.sup.21 to R.sup.27 is hydroxyl or amino group, at least one of R.sup.11 to R.sup.17 is sulfo group, and at least one of R.sup.21 to R.sup.27 is sulfo group; A and B are individually selected from the group consisting of hydrogen atom, alkyl (C.sub.1 -C.sub.4) groups, alkoxy (C.sub.1 -C.sub.4) groups, and halogen atoms.
There have also been reported some naphthol compounds considered "confirmed active" in AIDS antiviral screens. These include calcomine scarlet 4BNC (CAS Registry No. 5893323), direct fast scarlet 4BSW (CAS Registry No. 6420446), and brilliant paper scarlet G (CAS Registry No. 6460011). However, these just noted naphthol dyes all contain three or more sulfonic acid groups. The calcomine scarlet 4BNC, for example, is 2-naphthalenesulfonic acid, 7-[(4-aminobenzoyyl)amino]-3-[[4-[(2,5-dichloro-4-sulfophenyl)azo]-2-ethox y-6-sulfo-1-naphthalenyl]azo]-4-hydroxy-,trisodium salt (9CI).
Human immunodeficiency virus ("HIV"), a retrovirus in the lentivirus family, is believed to be the etiological agent of acquired immunodeficiency syndrome ("AIDS"). Chemotherapeutic strategies for treating AIDS or HIV infection have traditionally targeted critical enzymes in the viral life cycle. For example, HIV reverse transcriptase, which is necessary to convert the RNA-based viral genome to DNA, continues to be a target of drug therapy. More recently, the focus has shifted to multiple enzymatic targets such as the combination of reverse transcriptase and protease.
Currently used reverse transcriptase inhibitors fall into two categories. The nucleoside analogue inhibitors such as 3'-azido-3'-deoxythymidine ("AZT"), dideoxyinosine ("ddI"), and dideoxycytidine ("ddC") are deoxynucleoside mimics. These compounds are converted into triphosphate forms by intracellular enzymes and inhibit reverse transcriptase mediated DNA synthesis by acting as DNA chain terminators. However, presumably because of the cross reactivity with host polymerases, the side effects are notoriously severe and generally limit the therapeutic index of this class of drugs to relatively low levels.
The non-nucleoside inhibitors include nevirapine, tetrahydroimidazo-[4,5,1-jk] benzodiazepine-2(1H)-thione ("TIBO"), 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thimine ("HEPT"), and 2-pyridone derivatives. These compounds bind to an allosteric site on reverse transcriptase and are believed to inhibit the enzyme by affecting its conformational flexibility. Although this class of drugs has minimal side effects, because of the rapid development of viral resistance, these drugs become virtually ineffective typically within about six weeks.
In an effort to stem the development of viral resistance, combination therapies attacking multiple enzymatic targets have been recently advocated. For example, various protease inhibitors have been successfully combined with nucleoside inhibitors such as AZT and have reduced blood virus counts to virtually undetectable levels in some patients. However, this remarkable response is not reproduced in all patients. Moreover, in addition to the punishing side effects, users of protease inhibitors often must follow a demanding treatment regimen, with the risk that if a few doses are skipped, any advantage of the combination in stemming viral resistance may be lost.
The earlier noted U.S. Pat. No. 5,589,510 suggests use of its naphthalene sulfonic acid compounds in administration with other known HIV-reverse transcriptase inhibitors, such as AZT. Nevertheless, a need exists for new drugs against the HIV virus, particularly those that could be effective in inhibiting multiple enzymes necessary for the HIV virus. Ideally, these new drugs would only selectively target the virus and produce minimal patient side effects. Moreover, based upon the success of current combination therapies, the new drugs should be adaptable for use in such therapies by either attacking at novel targets for use with one or more existing drugs, or attacking multiple targets by themselves.